Brexpiprazole (Rexulti) in PTSD

Promising data, but failed at the finish line

STUDIES: Davis LL et al, JAMA Psychiatry 2025;82(3):218–227; Hobart M et al, J Clin Psychiatry 2025;86(1):24m15577; Davis LL et al, J Clin Psychopharmacol 2025;45(6):580-589.

STUDY TYPE: Randomized, double-blind, active- and placebo-controlled trials

FUNDING: Otsuka / Lundbeck (manufacturer of brexpiprazole)

Background

On September 20, 2025, the FDA rejected a new combination pill for PTSD, pairing the antipsychotic brexpiprazole (Rexulti) sertraline (Zoloft), an antidepressant that is already approved in PTSD. The trials were large, the results were positve, the medication was tolerable, so why the rejection?

▪ Only 1 out of 2 of the largest (phase III) trials were positive
▪ However, an earlier phase II trial was also positive

Let’s look at those trial results, starting with the earlier phase II trial. It was positive. The combo worked better than sertraline alone. But notice the high drop out rate. Generally we want those rates below 20%.

Next came the positive phase III trial. Surprisingly, the brexpiprazole-sertraline combo was better tolerated than sertraline alone, though weight gain and fatigue were more common. The drop out rate was also high.

Notice it took 10 weeks for brexpiprazole-sertraline to work. Most antipsychotics work within two weeks (although “work” here means separate from sertraline alone). Maybe it’s a fluke, or maybe brexpiprazole has a different mechanism in PTSD, not just reducing non-specific agitation as many of these meds do.

But those positive results were canceled out by a negative phase III trial:

Not Realistic

Mixed data is one thing. The FDA will often approve meds as long as two (or, in the post-2025 world, one) trials are positive (as it did with gepirone/Exxua). But here what really held it back.

These trials don’t reflect good practice. The participants had not tried medications for PTSD before, and they were started on the antipsychotic combo first-line. Sure, brexpiprazole was well tolerated in the short term, but we avoid antipsychotics first-line because of their long term risks like tardive dyskinesia, metabolic, and cardiac. 

Further, the study didn’t enroll the kinds of people we see with PTSD in practice. They excluded:

• Depression or other psychiatric comorbidities
• On psychiatric disability
• Trauma before age 16 (or trauma that was more than 9 years ago)
• Ongoing trauma
• Combat-related trauma was not excluded, but capped at 20% of the participants

Why remove people with depression? That’s fair, as brexpiprazole is effective in depression so we want to make sure their PTSD isn’t getting better because their depression improved. But it also skews the population, as most people with PTSD also have depression.

They also removed placebo responders, by giving everyone a placebo at first and removing those who responded. This helps detect a drug-placebo difference, but it also makes the population more artificial. Placebo responders are common in real practice.

About Brexpiprazole

Brexpiprazole (Rexulti) is an atypical antipsychotic already approved for schizophrenia, agitation in Alzheimer’s dementia, and as an adjunct for depression (however, it consistently failed in bipolar mania). It has broad activity across noradrenergic, serotonergic, and dopaminergic systems. In animal models, it reduced fear-avoidant behaviors after trauma.

Practice Implications

1. Brexpiprazole fails as an approved medication, but the positive signal in these trials places it among viable off-label options for treatment-resistant PTSD or PTSD with psychotic features.
2. Caveat: That off label use is not proven to work, but I say that with the understanding that no meds have proof to work in treatment-resistant PTSD (topiramate has some support).
3. Psychotherapy is first-line for PTSD. Among medications, some experts (including myself) recommend prazosin in many cases before FDA-approved options like paroxetine and sertraline. Find out why in the prazosin Carlat Podcast.